Chromosomal abnormalities II Flashcards
Structural abnormalities - list 7 types
Translocations - Reciprocal - Robertsonian Inversion Deletion Duplication Rings Isochromosomes Microdeletions/Microduplications
Describe formation of structural abnormalities
Double strand DNA breaks
Occur throughout cell cycle
Generally repaired through DNA repair pathways
Mis-repair leads to structural abnormalities
Reciprocal Translocations - define
Exchange of two segments between non-homologous chromosomes
So mechanism is called Non-Homologous End Joining (NHEJ)
Reciprocal Translocations - reason for its name = “non-homologous end joining”
The DNA repair mechanism is called “non-homologous end joining”: end joining because it’s joining together two ends and non-homologous because it’s irrespective of the DNA sequence joined together
These are also known as balanced translocations
Reciprocal Translocations - when
It’s thought that they form spontaneously during meiosis
Reciprocal Translocations - key characteristic
The key characteristic is that there is no net gain or loss of genetic material – it’s all there, just in a different place.
Reciprocal Translocations - which chromosomes involved
They can involve any chromosome and the fragments can be of any size
Reciprocal Translocations - incidence
They are relatively common – estimates suggest that they occur in 1 in 930 people
Balanced vs Unbalanced translocations
Balanced = have the right amount of each chromosome just maybe not in the expected place!
Unbalanced = too much or too little of a particular chromosome
Effect on carriers of balanced translocation - example
Philadelphia chr = abnormal chr22
Leads to Chronic myeloid leukaemia (CML)
ABL fuses w/BCR
BCR=breakpoint cluster region (Function of normal protein product not known)
ABL=protooncogene
Fusion of genes leads to an activated oncogene
Balanced translocation - define
Balanced translocation – no net gain or loss of material
Reciprocal Translocations - define
Exchange of two segments between non-homologous chromosomes
no loss or gain of material
Reciprocal Translocations - effect on phenotype
Usually no deleterious phenotype unless breakpoint affects regulation of a gene
Reciprocal Translocations - effect on carriers
Carrier of balanced translocation at risk of producing unbalanced offspring
Unbalanced individuals at significant risk of chromosomal disorder
How are unbalanced individuals produced?
Balanced carrier to unbalanced zygote
Consequences of reciprocal translocations
in meiosis
Chromosomes pair up before separating, form = pachytene quadrivalent = CS A + B with C + D (example)
CS separate along horizontal line, = one cell having a gain in A/B CS and a loss of the end of C/D CS;
the other daughter cell has a loss of the end of the A/B CS and gain of C/D
OR CS could separate along this vertical line
= an unbalance arrangement where, in each daughter cell, there is loss of one end of a chromosome and gain of the end of the other chromosome.
The exact consequences of inheriting a unbalanced rearrangement depend on what
The exact consequences of inheriting a unbalanced rearrangement depend on the particular chromosomes involved and the size of the translocated material.
Clinical result of unbalanced reciprocal translocation
Many lead to miscarriage (hence why a woman with a high number of unexplained miscarriages should be screened for a balanced translocation)
Learning difficulties, physical disabilities
Tend to be specific to each individual so exact risks and clinical features vary
Robertsonian translocation - define
When two acrocentric chromosomes break at or near their centromeres, when the fragments are joined together again it’s possible for just the two sets of long arms to be brought together and there’s loss of the satellites.
Robertsonian translocation - resulting number of CS
45
Robertsonian translocation - what is lost
The only genetic material we’ve lost are these satellites and the cell can do without those and so this isn’t a problem for the cell.
Robertsonian translocation - which CS effected
Only affect acrocentric chromosomes – ie. Those which have the centromere near the chromosome tip. These are chromosomes 13, 14, 15, 21 & 22
Robertsonian translocation - most common type + its result
Most common Robertsonian translocation involves chromosomes 13 and 14, which accounts for approximately 1/3 of all Robertsonian translocations
Results in loss of two short arms and fusion of the two long arms, with either one or two centromeres
The resultant chromosome usually contains the long arms of different chromosomes
What’s the centromere?
It’s the part of the chromosome which attaches to the spindle during cell division.
Robertsonian translocation - explain effect (balanced vs unbalanced)
Two acrocentric chromosomes join near centromere with the loss of p arms
Balanced carrier has 45 chromosomes
If 46 chromosomes present including Robertsonian then must be unbalanced
p arms encode rRNA (multiple copies so not deleterious to lose some)
Robertsonian translocations 13;14 and 14;21 relatively common. 21;21 translocation leads to 100% risk of Down syndrome in fetus
Robertsonian Translocation & Trisomy 21 - effect where one partner is carrier of robertsonian translocation
Can experience multiple miscarriages because of the way the chromosomes segregate,
= leading to loss of a chromosome or a trisomy which is incompatible with life
Robertsonian Translocation & Trisomy 21 - combinations and their effect
If you’re lucky, the gamete will contain the normal chromosomes, or the robertsonian chromosome
If you’re unlucky then the gamete will contain one of these combinations.
Most of them will be lethal
But upon fertilisation with a normal gamete, this cell will have 2 copies of chromosome 14, which is fine, but 3 copies of chromosome 21 – and will therefore be a Down’s baby.
This will be a “normal” Down’s baby in that the phenotype will be similar to a Down’s which is the product of non-disjunction.
Robertsonian Translocation & Trisomy 21 - when does it become a problem
However, it becomes a problem in the context of forming gametes, because although there’s the correct amount of genetic material, the chromosomes can’t segregate properly.
Outcomes of translocations
Very difficult to predict
- Only have approximate probability of producing possible gametes
Some unbalanced outcomes may lead to spontaneous abortion of conceptus so early that not seen as problem
Some unbalanced outcomes may lead to miscarriage later on and present clinically
Some may result in live-born baby with various problems
If the end of the chromosome is lost then the only way the chromosome can be made stable is what
If the end of the chromosome is lost then the only way the chromosome can be made stable is if a new telomere is added; without the telomere the cell will die
Inversion - define
An inversion is where there are two breakpoints within the same chromosome and when these are repaired the middle section is “upside down”
Duplication - define
A duplication is where you get a region of the chromosome repeated – you’ll probably be familiar with this in terms of the globin gene family
Ring CS - define
A ring chromosome is where you get two breaks in the same chromosome and that non-homologous end joining mechanism joins the two ends of the large chunk together, resulting in a ring.
Deletions - incidence of effect
1:7000 live births
Deletions - list types
Deletion may be terminal or interstitial
Deletions - genetic effect
Causes a region of monosomy
- Haploinsufficiency of some genes
- Monosomic region has phenotypic consequences
- Phenotype is specific for size and place on deletion
Deletions in relation to G-band
Gross deletions seen on metaphase spread on G-banded karyotype
Cri-du-chat - define
Genetic condition present from birth that is caused by the deletion of genetic material on the small arm (the p arm) of chromosome 5
Cri-du-chat - effect
ID, developmental delay, microcephaly
Microcephaly - define
Microcephaly is a condition where the head (circumference) is smaller than normal
Microcephaly - cause
By genetic abnormalities or by drugs, alcohol, certain viruses, and toxins that are exposed to the fetus during pregnancy and damage the developing brain tissue.
Microdeletions/Microduplications on metaphase spread
Many patients had no abnormality visible on metaphase spread
Microdeletions/Microduplications - result on from FISH, HRB and CGH
High resolution banding, FISH and now CGH showed ‘micro’ deletions
Contiguous gene syndrome - define
Only a few genes may be lost or gained – contiguous gene syndrome
A clinical phenotype caused by a chromosomal abnormality, such as a deletion or duplication that removes several genes lying in close proximity to one another on the chromosome.
Microdeletion syndromes - list 6
Velocardiofacial 22q11 (DiGeorge, Shprintzen) Wolf-Hirschhorn 4p16 Williams 7q11 Smith-Magenis 17p11 Angelman 15q11-13 (mat) Prader-Willi 15q11-13 (pat)
Array CGH - describe process
Pt and control DNA labelled w/fluorescent dyes and applied to microarray
Attached/hybridized to microarray
Microarray scanner measures fluorescent signals
Computer software analyzes data and generates plot
